Although we have gained understanding regarding spinal cord injury (SCI) and its underlying mechanisms, creating an effective therapy to minimize tissue damage and maximize functional recovery is still unrealized. The only available treatment, methylprednisolone (MP), has limited clinical efficacy. Thus, utmost emphasis should be on early pharmacological intervention to the secondary damage pathways involving free radical production, inflammation, ischemia, loss of blood supply, calcium (Ca2+) overload with downstream proteinase activation, and axonal damage. By investigating new treatments, novel therapies to block inflammation, reduce cell and axonal damage, and restore blood supply may be discovered. Oxidative damage, inflammation, and intracellular Ca2+ influx are implicit in the initiation of secondary injury pathways for cell death after SCI. By understanding SCI pathophysiology, rational therapies will be designed to pre- vent cell death, sparing greater portions of the spinal cord after injury. Since several pathways cause cell damage and tissue destruction, blocking only one may not be optimal. Therefore, combining several drugs will likely be more neuroprotective. Our goal is to protect CNS cells from secondary damage by combining agents that preserve tissue and promote functional recovery. We will use the anti-oxidant melatonin (MEL) with the anti-inflammatory MP and the novel calpain inhibitor SJA6017 (SJA). In addition, treatment with angiogenesis-promoting factors, e.g. vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGR. will promote increased blood supply to the injured cord and further aid in functional recovery after combination therapy. We hypothesize that MEL will prevent oxidative damage resulting from ischemia/reperfusion, lipid peroxidation, and monocyte phagocytosis;MP will prevent infiltration of inflammatory cells into the spinal cord;and SJA will prevent over-activation of calpain with the consequence of blocking downstream calpain-mediated apoptotic events. Including VEGF and bFGF in this combination will further promote recovery bv protecting cells from secondary damage.
Three specific aims will test the hypothesis: (1) examine the effects of MEL, MP, and SJA on the extent of cell death, inflammatory cell infiltration, white matter damage, oxidative stress, and calpain expression and activity following SCI;(2) using the parameters outlined in Specific Aim 1, investigate the efficacy of a triple (combination) therapy employing the treatments studied in Specific Aim 1, examine the efficacy in acute (48 hours) cord and in the weeks (chronic) following SCI by assessing white matter preservation and functional recovery;(3) investigate the mechanisms involved in angiogenesis and examine the effect of VEGF on capillary growth and blood supply following SCI and assess if addition of VEGF to triple treatment will offer maximum functional recovery after SCI.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS031622-16
Application #
7826740
Study Section
Clinical Neuroimmunology and Brain Tumors Study Section (CNBT)
Program Officer
Kleitman, Naomi
Project Start
1993-12-13
Project End
2012-05-31
Budget Start
2010-06-01
Budget End
2011-05-31
Support Year
16
Fiscal Year
2010
Total Cost
$316,182
Indirect Cost
Name
Medical University of South Carolina
Department
Neurosciences
Type
Schools of Medicine
DUNS #
183710748
City
Charleston
State
SC
Country
United States
Zip Code
29425
Samantaray, Supriti; Das, Arabinda; Matzelle, Denise C et al. (2016) Administration of low dose estrogen attenuates persistent inflammation, promotes angiogenesis, and improves locomotor function following chronic spinal cord injury in rats. J Neurochem 137:604-17
Samantaray, Supriti; Das, Arabinda; Matzelle, Denise C et al. (2016) Administration of low dose estrogen attenuates gliosis and protects neurons in acute spinal cord injury in rats. J Neurochem 136:1064-73
Thakore, Nakul P; Samantaray, Supriti; Park, Sookyoung et al. (2016) Molecular Changes in Sub-lesional Muscle Following Acute Phase of Spinal Cord Injury. Neurochem Res 41:44-52
Cox, April; Varma, Abhay; Banik, Naren (2015) Recent advances in the pharmacologic treatment of spinal cord injury. Metab Brain Dis 30:473-82
Cox, April; Varma, Abhay; Barry, John et al. (2015) Nanoparticle Estrogen in Rat Spinal Cord Injury Elicits Rapid Anti-Inflammatory Effects in Plasma, Cerebrospinal Fluid, and Tissue. J Neurotrauma 32:1413-21
Das, Arabinda; Guyton, M Kelly; Smith, Amena et al. (2013) Calpain inhibitor attenuated optic nerve damage in acute optic neuritis in rats. J Neurochem 124:133-46
Wallace 4th, Gerald C; Dixon-Mah, Yaenette N; Vandergrift 3rd, W Alex et al. (2013) Targeting oncogenic ALK and MET: a promising therapeutic strategy for glioblastoma. Metab Brain Dis 28:355-66
Varma, Abhay K; Das, Arabinda; Wallace 4th, Gerald et al. (2013) Spinal cord injury: a review of current therapy, future treatments, and basic science frontiers. Neurochem Res 38:895-905
Das, Arabinda; Wallace 4th, Gerald; Reiter, Russel J et al. (2013) Overexpression of melatonin membrane receptors increases calcium-binding proteins and protects VSC4.1 motoneurons from glutamate toxicity through multiple mechanisms. J Pineal Res 54:58-68
Smith, Joshua A; Park, Sookyoung; Krause, James S et al. (2013) Oxidative stress, DNA damage, and the telomeric complex as therapeutic targets in acute neurodegeneration. Neurochem Int 62:764-75

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